Acetal and ketal derivatives of j-



United States Patent ACETAL AND KETAL DERIVATIVES 0F S-(LOWER ALKGXYyA PREGNADIENE 1601,1711 DIiOlL-Zil- @NE Patrick Dlassi, Westfield, Null, assignor to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Nov. 17, 1961, Ser. No. 153,204

3 Claims. (Cl. 260-23955) wherein P and Q are hydrogen, lower alkyl, halogenated lower alkyl, monocyclic cycloalkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic, or monocyclic heterocyclic alkyl, or together with the carbon atom to which they are joined P and Q is cycloalkyl or monocyclic heterocyclic.

The compounds of Formula I are prepared by reacting a compound of the formula wherein P and Q are as hereinoefore defined, with a lower alkyl orthoformate such as ethyl orthoformate, butyl orthoformate and the like in the presence of an acid, such as sulfuric acid.

The starting materials for the process of this invention, i.e., the compounds of Formula II are prepared, by an acid condensation reaction disclosed in: Steroids, Feiser, p. 690 (1959); J.A.C.S. (Fried), vol. 80, 2338 (1958); and application Serial No. 774,607, filed November 18, 1958, now Patent No. 2,941,997, and Serial No. 774,615, filed November 18, 1958, now Patent No. 2,941,998, and Serial No. 775,388, filed November 21, 1958, now abandoned; by interacting 16oz,l7a-dihydroxyprogesterone with an aldehyde or ketone of the general formula:

in the presence of an acid catalyst.

Suitable starting materials are the 16a,l7oz-acetal and ketal derivatives of 16a,17m-dihydroxyprogesterone with a lower alkanal such as formaldehyde, t-rioxymethylene, paraldehyde, propanal and hexanal; or with a ketone such as di(lower alkyDketone, e.g., acetone, diethyl ketone, dibutyl ketone, methylethyl ketone, and methyliso- '3 fin butyl ketone; or a cycloalkanone such as cyclopentanone,

cyclohexanone, suberone and cyclooctanone; or a monohyde, acylamidobenzaldehyde (e.g., N-acetylanthranilal- 'dehyde), and cyanobenzaldehyde; a monocyclic aromatic lower alkanal, such as phenylacetaldehyde, a-phenylpropionaldehyde, fi-phenylpropionaldehyde, 'y-phenylbutyraldehyde, and aromatically-substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; a monocyclic heterocyclic aldehyde, such as alloxan, picolinaldehydes, furfural, thiophene carbonals, and halo, lower alkoxy, hydroxy, lower alkyl, nitro, and cyano derivatives thereof; a monocyclic hetero cyclic lower alkanal; a monocyclic aromatic ketone such as acetophenone, propiophenone, butyrophenone, valerophenone, isocaprophenone, halophenyl lower alkyl ketone (e.g., p-chloroacetophenone), (lower alkoxy)phenyl lower alkyl ketone (e.g., p-anisyl methyl ketone), di(lower alkoxy)phenyl lower alkyl ketone, hydroxyphenyl lower alkyl ketone, dihydroxyphenyl lower alkyl ketone (e.g., resacetophenone), a (lower alkyl)phcnyl lower alkyl ketone (e.g., methyl p-tolyl ketone), a di-(lower alkyD- phenyl lower alkyl ketone (e.g., o,p-Xylyl methyl ketone) a nitrophenyl lower alkyl ketone (e.g., nitroacetophenone), an acylamidophenyl lower alkyl ketone (e.g., acetyl-acetanilide), and a cyanophenyl lower alkyl ketone; benzophenone, and mono or his substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; a monocyclic aromatic lower alkanone, such as 1-phenyl-3-butanone and l-phenyl-4-pentanone, and mono or his halo, lower alkoXy hy-droXy, lower alkyl, nitro, acylamido and cyano substituted derivatives thereof; a monocyclic heterocyclic ketone (e.g., Z-acetylfuran, 2-benzoylfuran, and Z-awtylthiophene); a monocyclic heterocyclic lower alkanone; a halo-lower alkanal (e.g., chloral hydrate, tri-fiuoroacetaldehyde hemiacetal and heptafluorobutanal ethyl hemiacetal); or a halo alkanone (e.g., as 1,1,1-trilluoroacetone).

The compounds of this invention are physiologically active substances which possess progestational activity when administered either orally or parenterally in conventional dosage forms and hence can be used in the treatment of such conditions as habitual or threatened abortion as a substitute for and in the same manner as progesterone.

The following examples are presented to more fully illustrate this invention (all temperatures being in centigrade):

EXAMPLE 1 3 Eth 0xy-A -Pregnadi ens-1 6 0a,] 7oc-D 1' 01-20-0719 1 6 ,1 7-A cetonide To a solution of 1.00 g. (2.59 mmols.) of :,l7oc-dihydroxyprogesterone 16,17acetonide in 7.5 ml. of anhydrous dioxane, absolute ethanol (0.1 ml.) and ethyl orthoformate (1 ml.) are added. To this mixture, there is added dropwise a solution of 0.035 ml. of sulfuric acid in 0.7 ml. of dioxane. The reaction is left at room temperature for 15 minutes and then neutralized by the addition of 0.6 ml. of pyridine. Water is then added slowly whereupon 3-ethoxy-A -pregnadiene-160:,l7a-di0l- 20-one 16,17-acetonide separates in the form of long needles. These crystals are filtered, washed with methanol-water containing a drop of pyridine and dried, yielding about 978 mg. of product having the following properties: Ml. about 199-20 1 ARE? 240 mu (@:19,500); my 5.88, 6.00, 6.07, 6.18;;

Analysis-Calcd. for C H O (414.56): C, 75.32; H, 9.24; C-C H 10.87. Found: C, 74.94; H, 8.99; GC H 11.65.

In a similar manner, except for the substitution of an equivalent amount or" butyl orthoformate for the ethyl orthoformate of Example 1, there is readily obtained 3- butoXy-A -pregnadiene-16a,17ct-diol-20 one l6u,l7oc acetonide.

EYAMELE 2 16,1 7-A cezophenone Derivative of fi-Ethoxy-A Pregnadiene-I 601,1 7a-Dz'0l-20-One Following the procedure of Example 1 except for the substitution of the 16a,17c-acetopl1enone ketal of 16a,l7a-dihydroxyprogesterone for the aeetonide used in Example 1, there is obtained the acetophenone derivative of 3 -etl1oXy-160;,17u-dinydroXy-A -pregnadiene-ZD-one.

The corresponding p-chloroacetophenone derivative and p-nitro-acetophenone derivatives can be obtained by substituting in the procedure of Example 1, the p-chloroacetophenone derivative of 1 6a,l7oc-dihydronyprogesterone and the p-nitroacetophenone derivative of 16,17adihydroxyprogesterone, respectively.

ln a similar manner, by substituting the methylisobutylketone, methylethyl ketone, benzaldehyde furfural, benzephenone 2-acetal-furane, chloral, 1,1,1-trifluroacetone and the heptafiuorobutanal derivatives of 16,17e-dihydroxyprogesterone in the procedure of Example 1, the following are respectively prepared: 16a,l7a-n1ethylis0 butylketone derivative of 3-etnoXy-A -pregnadiene- 16e,17a-diol-20-one; 16a,17a-methylethylketone derivative of 3-etl1oxy-A -pregnadiene 16a,17e-diol-20-one; l6ct,l7c-benzaldehyde derivative of 3-ethoXy-A -pregnadiene-16e,l7cr-diol-20-one; 160:,1'7wf111'f11f21l derivative of 3-etn0Xy-A -pregnadiene-l60,l7e-dioi-20-one; 1606,1704- benzophenone derivative of 3-eti1oXy-A -pregnadiene- 160.,17a-di0l-20-0l16; 1 60.,17ot-2-acety1-furane derivative of 3-ethoxy-A -pregnadiene-l6a,17a-diol-2O-one; 1604,17- chloral derivative of 3-etl1oxy-A -pregnadiene-16m,17adiol-ZO-one; l6ot,17a-1,1,1-trifluoroacetone derivative of 3-ethoxy-A P-pregnadiene-l6e,17ct-dio1-20-one; and 16a, 17a-heptafluorobutanal derivative of 3-etl1o:-:y-A -pregnadiene-l6u,17ot-diol-20-one.

This invention may be variously otherwise embodied Within the scope of the appended claims.

What is claimed is:

1. Compounds of the formula:

CIT;

........O I) x (lower alkyl) O References Cited in the file of this patent UNITED STATES PATENTS Fried June 21, 1960 Ercoli Nov. 21, 1961 OTHER REFERENCES Cooley et 211.: 1.05. (London), 1955, pages 4373 4376.

Ercoli et al.: J.A.C.S., 82, Feb. 5, 1960, pages 746-748.

Notice of Adverse Decision in Interference In Interference No. 95,583 involving Patent No. 3,123,601, P. A. Diassi, AOETAL AND KETAL DERIVATIVES OF 3-(LOWVER ALKOXY)-N, 5-PREGNADIENE 16a, 17a-DIOL-20-ONE, final judgment adverse to the patentee was rendered May 6, 1968, as to claims 1, 2 and 3.

[Ofiicial Gazette August 20,1968] 

1. COMPOUNDS OF THE FORMULA: 